The role of gastric inhibitory polypeptide (GI) in glucose homeostasis has been further investigated in dog and man. The studies in the dog showed that the metabolic clearance rate of GIP was increased by hyperglycemia whether or not hyperinsulinemia was present, but that hyperinsulinemia alone did not influence the clearance rate. The suggestion that GIP might have an inhibitory effect on hepatic glucose output was not confirmed in these studies. Studies in man have been directed at the possible effects of hyperglycemia and hyperinsulinemia on the secretion of GIP in response to a fat meal. Ingestion of fat leads to elevation of the plasma GIP level and this elevation is uninfluenced by subsequent increase either in plasma glucose or in plasma insulin levels. However, the establishment of hyperglycemia and hyperinsulinemia prior to fat ingestion markedly decreases the GIP response to fat ingestion; hyperinsulinemia alone has no effect. The fat-stimulated GIP has no effect on plasma glucagon levels.